SA04250309B1 - A Pharmaceutical Composition for the Treatment of Cardiovascular and Cerebrovascular Diseases - Google Patents

Abstract

Abstract: The present invention discloses a pharmaceutical compound used to treat cardiovascular diseases and cerebrovascular diseases, as it includes Salviae Miltorrhiza root extract, Notoginseng root extract, Astragali root extract, and Borneol camphor or plant wood oil Lignum Dalbergiae Odoriferae. The present invention achieves remarkable effects against cerebral ischemia and myocardial ischemia, as these effects are better than those achieved by salvinolic acids or Notoginseng root saponins, whether they are given to the patient alone or in combination with other compounds. Components of the present invention can be formulated into several dosage forms by combination with one or more pharmaceutically approved adjuvants, thereby providing compounds from bioactive parts of herbs that are more suitable, more potent, and drug-derived from the same source for use in clinical applications.

Description

A pharmaceutical composition for the treatment of cardiovascular and cerebrovascular diseases ‎A pharmaceutical composition for the treatment of cardiovascular and cerebrovascular diseases Full Description Background The invention relates to a pharmaceutical composition. Specifically; The invention relates to a pharmaceutical composition used to treat cardiovascular diseases and cerebrovascular diseases. Numerous statistics showed that the morbidity rate and death rate due to heart diseases, Cardiovascular diseases, Ape and cerebrovascular diseases in China; It has been on the rise for the last five decades. During the fifties and sixties of the last century, cardiovascular diseases and yi yall cerebrovascular diseases ranked fifth and sixth among the diseases that cause death. It has increased since 19976, to occupy the second and third ranks, respectively. Cardiovascular diseases and cerebral vascular diseases dd yl cerebrovascular diseases rank first among the diseases that cause death. The death rate due to heart diseases, Cardiovascular and cerebrovascular diseases in China reached about 747.7 of the total deaths in the year 0011, after it reached about 717,097 in the year 175, and these days cause death of about? A million nasty people. Some Yyé¢e may survive

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sick from death; But most of them become helpless and unable to meet the requirements of their daily life

on his own; This makes them a heavy burden on their families and society. Cardiovascular diseases and cerebrovascular diseases are also among the most important causes of death in Western countries. According to recent epidemiological information; It is expected that coronary artery disease and cerebral hemorrhage will rank first and second among the diseases that cause human death by the year YoYo, although the ranks of diseases that cause death will change significantly. He expects that until then z; Coronary artery disease death rates will rise to 11 million by year 10 from 1.7 million in 1961 and brain hemorrhage death rates will rise to 0 out of 4; million to about 7./a million. Play these 30 years. J circular system diseases will increase death rates by 759.56. And death rates from coronary artery disease and stroke will rise to 7974.7 and Ave, respectively. All these data indicate that cardiovascular diseases and cerebrovascular diseases do not only pose a threat to human health. Rather, you will

ve "No. 1 killer" causing death or disability. Among the therapeutic drugs used in the treatment of cardiovascular diseases and cerebrovascular diseases are traditional Chinese medicines registered (in a patent) and Western medicines; Where these drugs are given to obtain results that focus on different features; Registered traditional Chinese medicines have fewer positive symptoms. That is why it consumes _0 more . Among the registered traditional Chinese medicines; And available for the treatment of heart diseases, Yves

- og those drugs ¢ cerebrovascular diseases and cerebrovascular diseases, which contain active ingredients from vital active parts of herbs; as β-notoginsenoside (from the sage plant); salvianolic acid succinic acid 8620 ¢ notoginsenoside

Cua ¢ gypenosides purarene roots ©0016:2:10” ¢ and glypenosides isoflavones are flavones that are attracting increasing attention. Since the bioactive parts of the herbs used in 0

Cardiovascular registered traditional Chinese medicines that are used in the treatment of heart diseases have acquired their own functions, cerebrovascular diseases and cerebrovascular diseases, and effects centered on many features; It is expected to be widely used in administering medicines and built-in Ula in a combined form. On the other hand, the registered traditional Chinese medicines used .on one biologically effective portion of the herb; Especially those in the form of solutions that are injected into the body, such as Xiusai Tong and Xiu Xuan Tong (trade names) - they are not available enough to be given to the patient in a combined form. in addition to; Mixing some registered medicines for use as solutions that are injected into the body without prior permission from the Food and Drug Administration of the Chinese government; It constitutes a great risk that may lead to the emergence of adverse reactions, such as a rapid rise in blood pressure; or a high body temperature or allergy. For this reason, it is important to provide effective and appropriate combinations of the biologically active parts of herbs for use in clinical applications. General description of the invention.

Thus, the current invention aims to provide effective and appropriate combinations - of biologically active parts - and preparations derived from the same source to be used in the treatment of diseases, where 00201078800127 diseases and cerebrovascular diseases Cardiovascular heart vy.

It becomes possible to overcome the shortcomings of traditional Chinese medicines that are registered and based on a single biologically effective part of the herb; Which cannot meet the clinical need for drugs that are given in a mane form, and side effects caused by mixing drugs with each other can be avoided. The present invention may be used as summarized in the following embodiments. 0 pharmacological composition of the present invention; Which includes: - Extract of Heda plant, Salviae Miltorrhiza; - Notoginseng root extract; - Aster root extract Jal 811 p 85088; And - Camphor Borneol or wood oil Dalbergiac Odoriferae. 0 is a preferred embodiment of the present invention; The composition of the invention includes_ of the following: 68 -..29750_ of the extract of the roots of the plant Salviae Miltorrhiza ¢ relief AY of the extract of the roots of the plant Notoginseng; Var — 6 Astragali Root Extract ; and Y.O. = 064 / of Camphor Borneol or oil add plant Dalbergiae Odoriferae. 1 A preferred AT embodiment of the present invention; The composition of the invention comprising the following: 6- ...78 _ of ADA the roots of the plant Salviae Miltorrhiza ¢

+ - Lo. - 6 Notoginseng Root Extract ¢ 6-..780 Astragalus Root Extract; And 0.8 = 217.3 of Borneol Camphor or Dalbergiae Odoriferae plant wood oil. A preferred DAT embodiment of the present invention; The composition of the invention containing the following: 66 ° = 2.2 _ of the extract of the roots of the plant Salviae Miltorrhiza; l of Notoginseng Root Extract ¢ 270.6 of Astragali Root Extract; And ZV of. Camphor Borneol or wood oil Dalbergiae Odoriferae. Another preferred embodiment of the present invention; The composition of the invention comprising the following: 1 “7_ of Heda extract of Salviae Miltorrhiza ¢ m of Notoginseng root extract; 7_ of Astragali root extract; And 4 of Borneol Camphor or Dalbergiae Odoriferae wood oil. and in another preferred embodiment of the present invention; Salvia Miltorrhiza Root Extract contains 0 10-7450 of cisminic acid 01 = JY « salvianolic acid salvianolic acid E » 771-74 manic acid lithospermic acid

Vv —_ _ 711-10 of seminal acid; And more than 7960 salvianolic acids. In another preferred embodiment of the present invention, it includes notoginsenoside R1 ZY +— ZX Notoginseng Ref. More than 7 - preferably more than 7280 - of Notoginseng root saponins and in another preferred embodiment of the present invention include Astragali Js! astragaloside I 710-50 ¢ and more than Ve Saponins from the roots of Astragali. and in a preferred AT embodiment of the present invention; Salviae Miltorrhiza root extract contains 0 more than 7860 salvinolic acids lia abl ¢ Notoginseng root extract includes more than LAY of Notoginseng saponins and Astragali root extract includes 1 L more than 00 Astragali root saponins.In another preferred embodiment of the present invention, the compound of the invention is in the form of injections; and fine granules.In another preferred embodiment of the present invention, the compound of the invention is in the form of injection or powder

M - The composition of the invention is used in dallas, cardiovascular diseases, and cerebrovascular diseases. Salviae Miltorrhiza Root Extract, which constitutes one of the aforementioned pharmaceutical ingredients, can be prepared by applying the process described in the following Chinese patents © TOYAAOCN Li D78 Helmc “To Per 01407 H and Guo Ying et al.” Journal of Yan'an University For Chinese medicine Yoo) gail;4(7):. It can also be prepared by applying other operations similar to those mentioned (cole) with some modifications added. Salviae Miltorrhiza root extract includes 40 1170-7 of 0 succinic acid 701-77 ¢ © salvianolic acid —a salvianolic “¢/— 0 lithospermic acid ¢ 710 -71 semen calculi; And more than 7970 = preferably more than 74846 - from salvinolic acids him aad. Apart from the process of preparing Salviae Miltorrhiza root extract, “Salviae Miltorrhiza root extract” here means that the components of the extracted substances fall within the registered targets; For this purpose, the extracted raw materials can be refined - by concentration, for example - until they are available in sufficient quantities as a component of the formulations. The compositions and their components can be distinguished and determined as follows: 1. Determine the contents of salvianolic acid, succinic acid, salvianolic acid, and lithospermic acid manic acid; and seminal acid in Y. Salviae Miltorrhiza (HPLC) root extract.

— a — a. Chromatographic conditions Filler: Octadecylsilyl-Silica Gel ¢ Mobile layer: acetonitrile - water - phosphoric acid ITY, 5 (20.0: 7..0); Detected wavelength: YAA nm. For theoretical plates not lower than ... m aly is calculated on the salvianolic acid peak e-sufficiency class. B. Preparation of control solutions: 17 mg/ml of succinic acid B salvianolic acid solution was prepared as a Java solution by mixing the control sample with the mobile layer. In a similar way, ¥ + falar ml of a solution of salvianolic acid, the control, is prepared; v.00 mg/mL of a 0-manic acid solution as a control; and 0,000 mg/mL of a control solution of seminal acid. z Preparation of sample solutions: A YO pile of Salviae Miltorrhiza root extract is weighed and placed in a YO ml measuring bottle. The mobile layer is added to the bottle - shake

Jay continuously - to dissolve the sample. The resulting solution is diluted by adding the mobile layer to Vo da Yo ll level of the solution with continuous shaking. Then a sample of © ml is taken and placed in a measuring bottle with a volume equal to eda YO, and the mobile layer is added to the bottle until the solution level reaches cde YO, and the resulting solution is shaken to mix well. : "s

— . \ _ Dr. The analysis process is to analyze 01 microliters of each control solution and each sample on the liquid chromatograph in the form of LY. Determination of succinic acids, salvinolic acids, in the root extract of Salviae Miltorthiza 0 383 above (measurement of the relative light intensity between different parts of Spectrophotometry A. Preparation of control solutions: 01 μg/ml of salvianolic acid solution is prepared by mixing the sample with a mixture of acetonitrile - water - phosphoric acid) 0.?? Mukalla T..) 0 b. Preparation of sample solutions: Yo mg of Salviae Miltorrhiza root extract was weighed and placed in a measuring bottle with an ana of +0 mL. And acetonitrile - water - phosphoric acid (YY.0) is added (mkalla T...) 0. The resulting solution is diluted by adding acetonitrile - water - phosphoric YY. 0 ) acid as “oe Y” until the level of the solution reaches yo ml - with simultaneous shaking 6 that occurs with the dilution process - after that a sample of ¥ ml is taken and placed in a measuring bottle of a volume equal to 50 ml; The mobile layer to the bottle until the level of the solution reaches (do YO) and the resulting solution is shaken to mix well. YY¢e¢

Find the analysis process:

Take acetonitrile - water - phosphoric acid 8.?)?: #.except: Y.+( as the void

“(blank) and the absorbance of control and sample solutions (IS) is determined separately under

A wavelength of YAA nanometers by measuring the relative light intensity between different parts of the spectrum.

China Pharmacopoeia) 0; 1440 edition (Vol. Gale) 7/8). Calculations are carried out by application

The following equation:

Salvinolic acids (%) 7 p (- b) + b

Where p is the correction factor and equal to a is the content of succinic salvinolic acids

acids, which is determined by measuring the relative light intensity between different caudal moieties versus 0 succinic acid B salvianolic acid; B is the content of succinic acid, salvianolic acid, which was obtained

Specified by HPLC*. HPLC Spectrum Spectrum of Salviae Miltorrhiza Root Extract

As for the method of determination, here it depends on the above clarification; associated with an acid

salvianolic acid b and e; as manic acid lithospermic acid ¢ and yo semen stone ¢ and the time period is determined by .1 minute.

Of all the distinctive peak points; The peak point of salvianolic acid was chosen

b; This is because it is large and stable. The relative retention time and relative peak area are calculated vs

The retention time and peak area of the reference peak point. There are 5-no normal peaks in dann

Salviae Miltorrhiza Root Extract; Specifically, there are +1 normal peaks.

11 - - The relative retention times for normal 1 peaks are in the order: 0.726-5.98 (salvianolic acid peak e) 0-113 (lithospermic acid peak 74-1 “ ( acid (peak of seminal acid); 7708 only Sal peak succinic acid 58171200116 B. The peak area of salvianolic acid B occupies between ZAY = 70V of the total peak area; its relative peak area is 1. when the retention time is relative between = cv.

Vo The peak area of the normal peak of lithospermic acid gallstones is approximately 218-77 of the total peak area; The relative peak area ranges from Yom 0 and the total peak area of the abnormal peak is less than 701 of the total peak area. (Say) Preparation of Notoginseng root extract - which constitutes one of the aforementioned pharmaceutical ingredients - by applying the process described in Chinese Patent 0011 Chinese Patent “17188017 A Qian Tian Xiang et al. Foreign Medical Sciences Department of Botanical Medicine 0441 4(17) Tang De Guang ve Journal of Traditional Chinese Medicine Registered -1446 (ANY 0<Standard of the Ministry of Public Health of China 0 WS 70011-7096 -8- (2) It can also be prepared by applying other processes similar to Causal above with some modifications. Notoginseng root extract is available in the market, for example it can be in the form of extract Form 730 (determined by UV ) than on notoginseng root saponins <Rgl 01 <Rb1) Notoginseng SRI AY. 0 0 215 ; determined by HPLC (Yves)

AY - - includes Notoginseng Root Extract /+=/Y Notoginseng from notoginsenoside R1 ¢ 1-7 from 7-711 « ginsenoside Re from 171-1101 (ginsenoside Rgl from cginsenoside 1 717 -75 of ginsenoside Rd « and more than 7970 - preferably more than 7850 = of Notoginseng Root Saponins. Notwithstanding the process of preparation of Notoginseng Root Extract; That the components of the extracted materials fall within the registered goals, and for this “pial”, the raw extracted materials can be refined - with concentration “She” - until they are available in sufficient quantities as one of the components of the formulations. The formulations and their components can be distinguished and identified as follows, respectively: LY Contents: «ginsenoside Rgl + notoginsenoside R1 «ginsenoside Rd «ginsenoside Re \ ginsenoside Rb] in Notoginseng root extract (HPLC) A. Conditions for chromatographic separation and system suitability testing Fillers: Octadecylsilyl-Silica Gel; Column temperature: 146 °C; flow rate: 0.7 mL/min; wavelength: 0.007 nm; the amount of mobile layer is: \o time water acetonitrile y 0 Vv 0 » y 0 7 0 1 0 0 ? q 0 1 0

B. Preparation of control solutions:

01.7 mg/mL of ginsenoside Re control solution is prepared by sample mixing

methanol control; In a similar way; Prepare +f mg/mL ginsenoside solution

LY Jalal Rd 11 mg/mL ginsenoside control solution; pala 0.4 / mm

° solution of notoginsenoside 881 ¢.” mg/ml of solution

ginsenoside Rbl control, respectively.

c. Preparation of sample solutions: Yo pile of Notoginseng root extract is weighed and placed in a bottle

Measurement with a volume equal to 00 ml. The mobile layer is added to the bottle - 01 is shaken continuously - to dissolve the sample. The resulting solution is diluted by adding the mobile layer until it reaches a level

the solution to 90 ml - while continuing to shake -

Dr. Analysis process:

01 μL of each of the standard and sample solutions is injected into a system

<HPLC and analyzed. Thus, the HPLC spectrum of the Vo 8 notoginseng root extract of this invention is obtained.

(1) Determination of Notoginseng Root Saponins in Notoginseng Root Extract

Notoginseng mentioned above (a measure of the relative light intensity between different parts of the spectrum).

Notoginseng Notoginseng Root Extract HPLC Spectrum Fingerprint (VY)

Vo — - for the method of determination here depends on the aforementioned illustration del and related to cginsenoside Re ginsenoside (Rd) ginsenoside (RT) notoginsenoside 1p and ginsenoside Rb1—above (1) Using JHPLC, the time period is set at 1 minute.

0 of all distinct peak points; The cginsenoside Rgl peak point was chosen because it is large and stable. The relative retention time and relative peak area are calculated against the retention time and peak area of the reference peak point. There are 9-17 normal peaks in the imprint of Notoginseng root extract; Exactly, there are 11 normal peaks. The relative retention times for the 11 normal peaks are in the order “A=VY (ginsenoside peak

(RI 01 L.Q » (tginsenoside Rgl peak 55.3) 1 ¢ (ginsenoside Rgl for reference peak) 1 4H under 1.31.47 (FFT. 0 peak (F. .¥-Y.40 ((ginsenoside Rbl D7-7 7 5559 Rd) (ginsenoside 1.7-91.. The ratio of the area of one peak to the total area of the peak is greater than 7780 only for the ginsenoside peak Rgl and .ginsenoside Rbl peak The area of the peak Vo of ginsenoside Rgl - the reference peak - is between -7708 75 of the total peak area; its relative peak area is .1 and the peak area of ginsenoside Rb1— U is between 7¥—766 total peak area; its peak relative area is 805.-7.90.the peak area of notoginsenoside R1 is about 78-77 total peak area; its peak relative area is 0.40-0.07. The peak surface area of RA notoginsenoside Ye is between ZY ¢=/o of the total area of the peak; the relative surface area of its peak is YYyée

- 11 from an area of 701, and the total peak area of the abnormal peak is less than .. 7- 4 the total peak. Which constitutes one of the components - Astragali The extract of the roots of the Astragali plant can be prepared in the aforementioned pharmacy - from Through the Application of the Process Described in the Chinese Patent (VIA RAY et al., West China Journal of Pharmaceutical Sciences, Yu Hao 01017776507, M. 5 Medical T.T., Mag.: Hei Long Jiang et al., Teng Journal Xing Long T1

EY :)0(70*7000 of Traditional Chinese Medicine Zhejiang 44S et al.; Journal of Wang Zhijie san plus coded and can be prepared by applying other processes similar to those mentioned Nia where 0 can be Market Astragali Modifications Astragali root extract is available as an extract containing between 798-7850 (UV determined) of 0. Astragali root extract contains 75-715 of astragaloside. And, Astragali, the extract of the roots of the Astragali plant contains more than 7970 - preferably more than 780 - of the saponins of the roots of the Astragali plant, “Notoginseng, regardless of the process of preparing the extract of the roots of the Astragali plant. Astragali The components of the extracted materials are “Astragali What is meant here by the phrase “the extract of the roots of the astragalus plant” ve, the raw extracted materials can be refined until coal falls within the registered goals, and for this reason it is available in sufficient quantities as one of the components of the compositions. The used in the above-mentioned composition can be either natural or synthetic Bomeol The camphor used in the composition can be Dalbergiae Odoriferae and the above-mentioned Dalbergiae Odoriferae wood oil can be obtained by distillation of the wood of the plant © spp

1- The components of the present invention can be formulated into several dosage forms by combination with one or more pharmaceutically approved aids. The aforementioned helper may be either starch or: dextrin, lactose, microcrystalline cellulose (avicel), hydrooxypropyl methyl cellulose (HPMC), polyethylene glycol, magnesium stearate, micro silicon gel, xylitol, lactitol, glucose, glycine, D- mannitol ° and the like - but it is not limited to what was mentioned -. The aforementioned pharmaceutical compositions can take several pharmaceutical forms, such as injections; discs; sweetened tablets; booster release discs; granules; injection powder; capsules; fine granules; and the like. Tablets are usually preferred; sweetened tablets; injection powder; and capsules. It is preferable that the total quantity of salvinolic acids with the saponins of Notoginseng roots and the saponins of the roots of the Astragali plant be more than JA in case the components of the present invention are formulated into injections or injection powder. The raw materials constituting the invention are easy to obtain; This facilitates the production of the compound of the invention in commercial quantities. The current structure can be formulated into several forms as desired. And ve provision of more appropriate modern registered traditional Chinese medicine. more effective; And of high quality for use in clinical applications. The present invention balances the effects of the invented combinations against cerebral ischemia; Salvinolic acids _ plus Notoginseng root saponins plus Borneol camphor or Dalbergiae wood oil ¢ Odoriferae 00 Salvinolic acids plus notoginseng root saponins

- 1 pm

Notoginseng; Salvinolic acids and saponins of notoginseng roots

Notoginseng using a localized cerebral anti-ischemia model; Allg caused by mode

Ferric chloride (IT) hexahydrate applied topically to the midbrain artery; and identify symptoms

The nerve and the violated cerebral region. The results indicate that the current compound has a significant anti-cerebral ischemia effect. Cua has more effective effects than salvinolic acids

alone or Notoginseng root saponins; More effective than acids

Salvinolic acids plus Notoginseng root saponins » and more

An effect of succinic acids, salvinolic acids, plus Glial aa, notoginseng roots

Notoginseng plus camphor Borneol or wood oil Dalbergiae Odoriferae. The results indicate that for the pharmaceutical composition of the present invention - eg mixing the extract of the roots of the saliva plant

Miltorrhiza 581»186_plus Notoginseng root extract plus

Extract of the roots of the Astragali plant and Camphor Borneol, or the extract of the roots of the plant

Saliva Miltorrhiza P581 »18_ plus Notoginseng root extract plus

Astragali Root Extract and Dalbergiae Odoriferae Wood Oil - 1 Remarkable synergistic effect. :

Brief description of the graphics

Figure 1: HPLC fingerprint spectrum of Salviae Miltorrhiza root extract

(0-1 minutes)

Figure ?: Spectrum of the 1101.0 fingerprint of Notoginseng root extract (01- Lia) Notoginseng

minute).

‎YYé¢

In all recipes of the present invention; The unit of all ratios is weight, unless it is stated otherwise. The invention will be better understood if reference is made to the examples that will be given shortly. The examples are intended as a sill and are not intended to limit the scope of the invention. Example 1 © Salviae Miltorrhiza Root Extract : Salviae Miltorrhiza Root Extract is prepared in the manner described in Chinese Patent Application 49444801 Jd) AY by grinding 0 kg of Salviae Miltorrhiza roots into a coarse powder and then extracted with de-ionized water at a temperature of 100 m in Alla at a mild boil. During the extraction process J TY.0 kg of water is added and heated for 1 hour; For the second and third extraction processes, 15 kg of water is added and heated for half an hour, respectively. The acidity is set to a pH? with HC /0 and then filtered. The filtrate is then loaded onto a polyamide resin column (the amount of dry resin equals two-thirds of the crude extract). The column is sequentially purified with deionized water of five times the volume of the column; followed by a solution of Le NaHCO; \o is five times larger than gall 3 . The resulting sequential purification is collected to be carried on an absorptive resin with large pores: 110 after bua has its acidity on Y pH using + HCL ZY, then the resin is sequentially purified using de-ionized water until the acidity of the resulting purification is neutralized sequential. The column was then purified with 300 pounds ethanol, after which a strip was collected

— ov. -

the color. The solution is concentrated under reduced pressure until it is completely dry. Then the dry matter is dissolved in water and kept in the refrigerator overnight. After being filtered through a microporous filter membrane (pore diameter 1 nm) made of mixed cellulose; We obtain an extract of succinic acids 881100116 . Its acidity was adjusted to 3 using a solution of 11201177 d, and it was dried immediately in the state of freezing (le) (low pressure) to obtain 771 gm of dry and frozen powder from the extract of the roots of Salviae Miltorrhiza. The output contains

6 Salviae Miltorrhiza raw material. The root extract of All Salviae Miltorrhiza obtained contains salvianolic acid a-salvianolic acid b “0 salvianolic acid c salvianolic acid 3 ¢ succinic acid 41 58171800116 E. succinic acid, salvianolic acid, melithionone 1, manic acid, lithospermic acid; gallstone acid » 20806050l; and so on. Where the ratio of succinic acid salvianolic acid to 7287.977 to succinic acid salvianolic acid e 77.7 as manic acid ¢/0.Y lithospermic acid to seminal stone acid vo and succinic acids formed salvinolic acids 7487.94. The HPLC spectrogram of the root extract of Salviae Miltorrhiza showed + normal peaks (average of 01 batches). The averages are the relative retention times for these six peaks; Respectively; are: 1.60 (peak succinic acid +A ((—a salvianolic | acide! (peak lithospermic acid)); 01 (peak semenic acid); 1 (peak succinic acid salvianolic acid 0 _ b) VL vA 1.776 The ratio of the area of one peak to the total area of the peak is greater than 771 only for the peak of succinic acid salvianolic acid b. It occupies an area

to "9"4

Y \ — — peak for salvianolic acid in 7a/(modified) total area of the peak; Its relative peak area is 1; the peak area of lithospermic acid gallstones occupies approximately 1/00 (average) of the total peak area. The total peak area of the abnormal peak J is 701 of the total peak area. The HPLC fingerprint spectrum of Salviae Miltorrhiza Root Extract is shown in Figure 1. Notoginseng Root Extract: Commercially available Notoginseng root saponins (Jaa) are refined on Notoginseng root extract. Notoginseng. This extract contains: ginsenoside Rb1, ginsenoside Rd, ginsenoside Re, ginsenoside Rg1, ginsenoside Rg2, ginsenoside Rg3, ginsenoside Rh1, ginsenoside Rh2, panaxytriol, notoginsenoside R1, Ve notoginsenoside R2, notoginsenoside R3, 20-gluco- ginsenoside Rf., where the ratio of ginsenoside Rb1 “/Y£.Y ginsenoside Rgl “/¥.4 ginsenoside Re notoginsenoside R1 “ZA.A ginsenoside Rd “ / 7/1.86 0 and the saponins of Notoginseng roots 794 ve HPLC fingerprint spectrum of Notoginseng root extract showed 11 normal peaks (with a rate of 0 batches). The averages are the relative retention times for these 11 peaks; on “can ill is: AY + (¢(notoginsenoside R1 peak 14”) (peak 1 “(ginsenoside Re (ginsenoside Rgl peak reference peak)); Y.A0 (Rb] ( 44 T Kha E (ginsenoside Rd peak ) and YA .¥ .4585 (peak area ratio)

YY - - one to total peak area greater than 7708 only has 35.3 ginsenoside Rgl and .ginsenoside Rbl peaks and ZY A ginsenoside Rgl (modified) peak area occupies the total peak area; Its relative peak area is 1 . dal ue peak 1i ginsenoside occupies 779 (modified) of the total area of the peak; Its relative peak area is VY (rate) Jonny. The area of this peak is 1 1/11 notoginsenoside (rate) of the total peak area; Its relative peak area is 0718 (average). The peak area occupies 701 ginsenoside RAJ (modified) of the total peak area; Its relative peak area is 0.397 (average). The total peak area of the abnormal peak is less than 700 of the total peak area. HPLC fingerprint spectrum of Notoginseng root extract shown in Figure 1.0 Astragali root extract: The commercially available Notoginseng root extract, Jani, is refined on root extract Notoginseng plant containing: acetylastragaloside, astragaloside I, astragaloside II, astragaloside III, astragaloside IV, isoastragaloside I, isoastragaloside II, astramembrannin II, cycloastragenol, soyasaponin I, lupeod, [beta]-sitosterol, daucosterin. \o where astragaloside I 1.0 / and the contents of dada formed the roots of the JAAS Astragali plant © / mg of Salviae Miltorthiza root extract is mixed; Pale) 01 of Notoginseng Root Extract » #l/mg of Notoginseng Root Extract

Astragali — all of which were obtained by applying the above- vo, amalgam of Borneol camphor « being sufficiently mixed. It is then freeze-dried (eg 1 ° mixing pale 001 of Salviae Miltorrhiza root extract; 100 mg of pile VO « Notoginseng of Astragali root extract - Obtained by following the method shown in the example - and 0 * mg of wood oil, Dalbergiae Odoriferae ly “¢ with + + ; mg of polyethylene glycol-6000” and melted to give a mixture. This mixture is left to cool and thus we obtain On the compound of the invention, for example? On it by applying the method shown in Example 1 - and YA amalgam of camphor 3000601; Cus the mixture is stirred sufficiently. It is dried in Alla antifreeze (at 010 low pressure) to obtain a compound to choose | p Example 4 Vo is mixed 100 mg of Salviae Miltorrhiza root extract YOu « Salviae Miltorrhiza mg of Notoginseng root extract 0009 mg of Astragali root extract - Obtained by applying the method shown in Example -1 and Yyeee

100 mg* of Camphor, Borneol; where it is sufficiently mixed. And it is dried in the state of freezing (for example o Mixing V0 mg of the extract of the roots of Salvia Miltorrhiza A + “Salviae Miltorrhiza” mg ©. of the extract of the roots of the Notoginseng plant Notoginseng 00 mg of the extract of the roots of the Astragali plant - Obtained by applying the method shown in Example -1 and Yo mg of camphor 300601, where they are sufficiently mixed and dried in a solid state (Example 1

01 Vo mg of Salviae Miltorrhiza root extract is mixed; 018 mg of Notoginseng root extract; axle AY from dada roots of the Astragali plant - obtained by applying the method shown in Example -1 and PA pile from Borneol camphor; Cus is sufficiently mixed 0 and freeze-dried (on

Vo for example

771 mg of the extract of the roots of Salvia Miltorrhiza VO « Salviae Miltorrhiza mg is mixed

Notoginseng root extract; 11 mg of plant root extract

Astragali - Obtained by applying the method shown in Example -1 and 8 YY颢

— 7 o — mg of Camphor Borneol; Cua is sufficiently mixed. Freeze-dried (example A) Mix VY mg Saliva miltiorrhiza 11028 pale 00 1 Salviae from © Notoginseng root extract 48 + 101 mg Astragali root extract - Obtained by applying the method shown in Example -1 and 0 mg of Camphor Borneol where it is sufficiently mixed 0 and dried in a freeze state (for example q 1) 00 mg of extract of 011 ¢ Salviae Miltorrhiza roots Notoginseng root extract 713 mg Astragali root extract - Obtained by applying the method shown in Example -1 and 8 mg of Borneol camphor Where it is sufficiently mixed 0 and dried in the state of freezing (for example 01 \o mg 1 1 1 Salviae Miltorrhiza 17 mg of Salviae Miltorrhiza root extract is mixed 17 mg of root extract of Salvia Miltorrhiza 01 mg ; Notoginseng from the extract of the roots of the plant Notoginseng obtained by following the method shown in the example - and ?8 mg - Astragali astragali

YY¢

of Dalbergiae Odoriferae wood oil «with 400 mg of polyethylene glycol-6000» and melted to give a mixture. This mixture is left to cool and thus we get the compound of the invention. Example 11 Pale Ve is mixed with Salvia miltórrhiza (pala) root extract © ¢ Salviae Miltorrhiza from © Notoginseng 900 mg of Astragali root extract - obtained by following the method shown in the example -; and 0,000 mg of wood oil of the plant Dalbergiae Odoriferae ; With »+ £ pile of polyethylene glycol-6000 0 and melt to give a mixture. This mixture is left to cool and thus we get the compound of the invention. Ex 11 01 Pale 165 of Salviae Miltorrhiza ¢ 000 mg of Notoginseng root extract is mixed; 01 mg of Astragali root extract - obtained by following the method shown in example y = © ? mg of wood oil of Dalbergiae Odoriferae ; With + + pilaf of polyethylene glycol-6000 « and melt to give a mixture. This mixture is left to cool and thus we obtain a compound Cel \o Example VY Vo mg of Salviae Miltorrhiza root extract is mixed; © 1 mg Notoginseng Root Extract; AY mg of Astragali Root Extract - Obtained by the method shown in the example -; and ALFA Yves

from the wood oil of the Dalbergiae Odoriferae plant; With + + pilaf of polyethylene glycol-6000 «and melted to give a mixture. This mixture is left to cool and thus we get the compound of the invention. EXAMPLE 4 1 771 mg of Salviae Miltorrhiza root extract is mixed; © to mg of oo Notoginseng root extract ails VV » Notoginseng from Astragali root extract - obtained by following the method shown in the example A yom mg of wood oil of Dalbergiae Odoriferae ¢ with + + mg of polyethylene glycol-6000 and melted to give a mixture. This mixture is left to cool and thus we get the compound of the invention. Example Yo Ve VY mg of 0 ¢ Salviae Miltorrhiza root extract is mixed with 0 mg of Notoginseng root extract; pale 771 from the extract of the roots of the plant Astragali - obtained by following the method shown in the example -; And 1 mg of wood oil of Dalbergiae Odoriferae ¢ with ++ £ pila of polyethylene glycol-6000 and melted to give a mixture. This mixture is left to cool and thus we get the compound of the invention. Vo Example A 100 mg of Salviae Miltorrhiza root extract is mixed; axle) Ve of Notoginseng root extract 17 mg of Astragali root extract — Lele is obtained by following the method shown in the example -; And 48 mg Yvée

of wood oil of the Dalbergiae Odoriferae plant with £++ mg of polyethylene glycol-0 and melted to give a mixture. This mixture is left to cool and thus we get the compound of the invention. Example 11 VO gm of Salviae Miltorrhiza root extract is mixed; © 0110 g of Notoginseng root extract 048 97 g of Astragali root extract - obtained by applying the method shown in Example 1 -; and Yo 3000601 0 g of camphor 0 g of mannitol ¢© } g of calcium disodium edate ¢ and 1001 mL of distilled water, mixing adequately. It is freeze-dried le (low pressure) and divided into 1 * 0 * 0 0 perfect denominator (without residue) 0

YA JE 01 with an application (Salviae Miltorrhiza of Salvia Miltorrhiza root extract TV Lali any 1 g of root extract of YA plant for 1 as stated in the Chinese patent 65a to an example of a g of root extract of a plant TY of the invention)” 1 (Ex. Notoginseng mix this Cua ; Borneol of the invention); and 11 g of 1 camphor (eg Astragali microcrystalline cellulose 00 gm microcrystalline cellulose). The ingredients are well combined with 1

IA to soften the mixture. The mixture is passed through a povidone-ethanol ZY sieve, then a solution is added to form granules, which are dried at a temperature of 10°C for a period of >50 minutes. Then the mixture is stirred. packing the resulting granules in tale pruning the resulting granules; and added; gm of "1 m

- Ya - Example va Take 0 g of Salviae Miltorrhiza root extract (prepared according to the water extraction and precipitation method Jnl Guo Ying et al.; Journal of Yinan University CL 5 Traditional Chinese 10 + ( : ( ¢ ) Ye 010 g Notoginseng et al.; Foreign Medical Sciences; Department of Botanical Medicine 9541 00 o(£)VY g Astragali Root Extract ( Example 1 of the invention); and 0 mg of Borneol camphor; each is dissolved separately in a small amount of physiological saline. An appropriate amount of Ae tween is added each mixture is finely ground; 0 is removed The color from it after the physiological saline solution is added to it.Then the solution is filtered under low pressure until it becomes clear and transparent.Then the filtrate is collected in a container containing the physiological saline solution.The container is closed and sterilized with boiling water.Then the three solutions are mixed and the acidity of the mixture is adjusted to pH 5. Then the appropriate volume of physiological saline is added, and the filtration process is repeated until we obtain a clear and transparent cilia solution, thus we have obtained the syringe. required yo

Yoo Jud (prepared with Salviae Miltorrhiza 0 gm extract of Salvia Miltorrhiza root extract) ; Example AVFAE AON by applying what was stated in the Chinese patent and others » Journal of Chinese Medicine ad se (Tang de Notoginseng, the roots of the plant Notoginseng, 165 g of the extract of the roots of the Astragali plant, 165 ») (8:)8(17) 0446 and traditional 3

Alice 1e (Example 1 of the invention) “and ©? mg of Camphor Borneol where these components are mixed well with 560 gm of microcrystalline cellulose. A solution of 77 povidone-ethanol is then added to soften the mixture. The mixture is passed through sieve #08 to form granules, which are then dried at a temperature of 60°C for 50–70 minutes. The resulting oo is then trimmed; and added; gm of tale and stir the mixture. The resulting granules are pressed into tablets. Example YY

0 gm of Salviae Miltorrhiza root extract is taken (it is prepared

Applying what was stated in the Chinese patent 1,740,800; VO) Jal Gman

0 A Notoginseng root extract (Example 1 of the invention)” AY gmmen Astragali root extract (Example 1 of the invention); And 4 pale of Camphor 30001, where these ingredients are mixed well with Er gm of microcrystalline cellulose. A povidone-ethanol ZY solution was then added to soften the mixture. The mixture is passed through sieve #08 to form granules, which are dried at a temperature of 10 m for a period of time.

YO 10 £4 min. Then the resulting granules are trimmed and added; gm of tale and stir the mixture.

YY example

AO is mixed with a gram of Salviae Miltorrhiza root extract (by applying

The Chinese patent states cAVFAL ALCON Example 1); 18 g of Notoginseng root extract 148 (Example 1 of the invention)”

007 Medical Hei Long Jiang et al. ¢ Journal of Teng Xing Long) Astragali Astragali 0

YYs ¢

Dose 1:(0) and 70 gm of Borneol Camphor; Where these ingredients are mixed well with 0 gm of polyethylene glycol-6000; And it is melted. Then it is dropped into low-temperature liquid paraffin; Then the resulting grains are selected and removed from liquid paraffin at low temperature.

Example YY Mix VY g of Salviae Miltorrhiza root extract (applying the Chinese patent cAVYAL ACN Example 1); 7860 g of Notoginseng root extract (Example 1 of the invention)”; VY g of Astragali root extract (Example 1 of the invention; Extraction: 1180 (Als Yu Western Journal of Pharmaceutical Sciences; ¢V1Y:)©(48 ©0947) _Refining: yg aly Teng Xing Long Hei Long Jiang Medical Journal; (0)V0 007 46 ); and VU gram of Camphor Borneol ; Cua mix these ingredients well with 0060 gram of polyethylene glycol-6000, melted, then dropped into low temperature liquid paraffin, and then selected

The resulting grains were removed from liquid paraffin at a low temperature. Vo example Cove: TV is mixed with a gram of Salviae Miltorrhiza root extract (by applying what was stated in the Chinese patent (cAYYOTYAAOCN Example 1); 080 g of Notoginseng root extract (Example 1 of the invention)”; TV g of Astragali root extract (Example 1 of the invention); and 11g of Dalbergiae wood oil 0g08:000; Cus mix these ingredients well with 400g of cellulose crystalline flour

Alice microcrystalline cellulose. A solution of 77 sovidone-ethanol is then added to soften the mixture. The mixture is passed through sieve #18 to form granules, which are then dried at a temperature of 1 m for 5?-40 minutes. The resulting granules are then trimmed; to be added afterwards; gm of tale and stir the mixture. The resulting granules are packed into capsules. ° Example Yo is taken 0 g of the extract of the roots of Salviae Miltorrhiza (it is prepared by applying what was stated in the Chinese patent 0445646017 – Example Aro) of the root extract of Notoginseng (Notoginseng) Tang De Guang et al. » Journal of Recorded Traditional Chinese Medicine; 1440 “(5:)4)11.119 g of Astragali root extract 0 (Example 1 of the invention); and YO mg of Cu) wood of the Dalbergiae Odoriferae plant, where these ingredients are mixed well with fr a gram of microcrystalline cellulose. A solution of 77 povidone-ethanol is then added to soften the mixture. The mixture is passed through sieve #08 to form granules, which are dried at 60°C for YO 0 minutes. The resulting granules are then trimmed; and added; of tale and stir the mixture. vo The resulting granules are pressed into tablets. EXAMPLE 7 908 g of Salviae Miltorrhiza root extract (prepared by application of Chinese Patent 1845866017 EXAMPLE 1) are taken; 150 g of Notoginseng root extract (EXAMPLE 1) of the invention); 87 g extract of ve roots of the Astragali plant (Example 1 of the invention); Ag mg of plant wood oil

Copy A gram of cellulose flour fe, where these ingredients are mixed well with Dalbergiae Odoriferae povidone-ethanol 77, after which a solution is added. microcrystalline cellulose 18 degrees Slo to form granules that are dried to soften the mixture. Pass the mixture through a measuring sieve and add; a gram of dail) a minute. Then the granules are trimmed at 40 STO m for 1 heat, after that the resulting granules are trimmed and packed in cans. Ad The mixture is stirred; tale ©

YY Example with an application (Salviae Miltorrhiza g of root extract of Salvia Miltorrhiza Ao being mixed in Chinese Patent 8174409067 Example 1); 175 g Root Extract 1 g Av (pla) Root Extract (ex. Notoginseng 1007 Medical Hei Long Jiang et al.; Journal of Teng Xing Long) Astragali Ve; Where these Dalbergiae Odoriferae gm of Yo wood oil and (YE:)(0) are mixed and melted. Then polyethylene glycol-6000 gm of 00000 ingredients are mixed well with a temperature low, and then liquid paraffin is picked and dropped into low-temperature liquid paraffin. liquid paraffin the resulting grains and removed from liquid paraffin

YA Example \o with an application ( Salviae Miltorrhiza WILL 11 g of root extract is mixed

Gly root extract 180 of) 817740 m; An example of ACN came in the Chinese patent “g of the root extract of the VY plant of the invention”); ( Astragali Astragali et al.; Teng Xing Long China Journal of Pharmaceutical Sciences; 14487 2(48): 167; Refining: _

$wv — — Hei Long Jiang Medical; 0707 2(0)V0 46)” and VT gm wood oil <Dalbergiae Odoriferae where these components are mixed well with 100 gm of polyethylene glycol-6000; And it is melted. Then it is dropped into low temperature liquid paraffin; The resulting grains are then selected and removed from the low temperature liquid paraffin©. Experiment 1- Effects of pharmaceutical compounds of the present invention on localized cerebral ischemia 1. Materials and devices: J Animals: male Sprague-Dawley (SD) rats; weighs between 1880-000 g Ve Quality Control Certificate No. 2002-0003 SCXK (Beijing); Awarded by Beijing Weitong Lihua Experimental Animal Technology Company; Ltd. B. Tested drugs and chemical agents: : Tested drugs: The structure obtained Ade in Example 1 and Example ?; Root extract of Salviae Miltorrhiza in Example 1; Root extract of Vo Notoginseng in Example 1; Astragali root extract in Example 1; Wood oil of Dalbergiae Odoriferae and Camphor Borneol. 6 (trading cm) is bought from the market; Manufactured by Quuming Pharmaceutical Co., Ltd. (lot) ic gana No. 0.1.0101

Yo — | Set (lot) No. Bella c. Experimental equipment: XTT stereomicroscope; Produced by Yunnan Optical Instrument Factory; Model 7700-8176 Analytical Electronic Scale; Japan Shimadzu Dental Cart 1-7.7, Shanghai Dental Instrument Factory; Vibrating air bath (HZQ-C) Produced by Harbin Dongming Medical Devices Factory. LY Application steps and results A. Collecting and giving the products to be tested: The volumes are randomly distributed into 0 groups according to weight. All animals in the groups are given energy The products to be tested were administered via the sublingual vein Fe minutes after the surgical procedure The tested products could also be injected between the peritoneal membranes of test rats 2 hours and YY hours after the surgery All the products were diluted with saline physiological to the desired concentration.The injection dose is given in the amount of 100 [de 04 gm of body weight.

1 b. Mid-cerebral artery occlusion model: rats are anesthetized with Yoru 701 chloral hydrate solution (mg/kg) through the peritoneum; It is positioned on its right side. A curved incision of 019 cm length is made from the point between the outer edge of the left eye and the left external auditory canal. the temporalis muscle is removed; revealing the temporal bone; Under the stereoscopic microscope, a small narrow incision was opened in the bone with a diameter of 7.5 mm in the joint between the zygomatic bone

0 The squamous temporal bone is located 1 mm from the mouth end of the joint. After getting rid of the residue

S -

debris and exposing the midbrain artery - which lies between the olfactory bundle and the intercerebral vein -;

A small piece of plastic wrap is placed to protect the area around the blood vessel. and then

A small piece of quantitative filter paper soaked with 10 μl of ferric chloride (1) is placed over the

This part of the midbrain artery; and after Te min; The filter paper is removed and the tissue is washed

surrounding the physiological saline solution and suturing the wound over several layers. The rats are returned to their cages

in a natural growing environment. The room temperature is fixed to YE m.

c. Recording measurements of neurological symptoms

Behavior was evaluated 1 hour after YE; Where the registration measurements were as follows: (1).

Observing the position of flexing the forelimbs after raising the rats by their tails; No point is scored if 0 forelimbs extend forward symmetrically; 1 point is scored if a shoulder sprain is observed;

elbow sprain; and (or) flexion of the shoulder on the anterior limb located on the opposite side of the site

perform the operation. (7) Placing the rat on a flat surface pushing its shoulders towards the opposite side (Dandy).

Resistance. No point is scored if the resistance is equal and intense in both shoulders; A point is scored

One if the resistance decreases on the opposite side of the operation site. (¥) Place the rat’s forelimbs 1 on a metal grid and observe the muscle tension. No point is scored if the muscle tension is

equal and strong at both ends; One point is scored if the muscle tension of the forelimb decreases

It is located on the opposite side of the operation site. (;) One point is scored if the mouse rotates in a shape

Continuing towards the opposite side of the operation site in case it was raised from its tail.

Based on the above recording measurements; lef The sum of the points is ;. The higher the total points; The more severe the behavioral deficit.

Name - Dr. Determining the extent of cerebral infringement The rats are decapitated after completing their behavioral assessment. brains are collected; removal of the olfactory bulb; the cerebellum; the lower brain stem; The remainder of the brain is cut into 0 sagittal slices. Five brain slices are immersed in TTC dye solution (each © ml of 0 dye solution contains 0.8 ml of 74 1.0 “TTC ml of 1 Mol 16211707; distilled water is added until the solution level reaches © Ml); and kept in an incubator at a temperature of 71 C in the dark for 0 minutes; Then the brain slices are placed in a solution of 7010 formaldehyde and kept in the dark for an hour. And by the act of dyeing; The color of the ischemia is pink-red; While the ischemia is white. White tissue from brain slices is carefully removed and weighed. 0 The relative weight of the infringed tissues in the whole brain and in the affected side of the brain is seen as the extent of the cerebral infringement.

rs h. RESULTS: Table 1 Effects of pharmaceutical compounds and extracts of the present invention on neurological symptoms in rats (sxx) (MCAO) dosed groups | number | Symptoms result | Symptomatic outcome (mg/kg of | animal | bacilli after 1 | nervousness after 76 body weight) at hrs. Pharmaceutical formulation shown in Example 1 (Saliva miltiorrhiza root extract Sex +77 Vo | Y+o+y. +o | Salviae Miltorrhiza Aloeh,*»« Camel jabour plant 88 @sast 48 + Astragali plant roots + Camphor Borneol ( cas Pharmaceutical shown in the example ¥ (extract of roots of Salviae Miltorrhiza + Extract of plant roots | E15+0+E+? | Vo 7 E Mex, | Buzz Yah ** 8 + Roots of plant 828 5#© 1 + Oil of wood (Dalbergiae Odoriferae) Roots of Notoginseng + Camphor #8 Borneol Root Notoginseng # err] | dae] Yy¢s

~ vq — Note: SPF 5...; cou 0 V3 PEF compared to the control group; * ME < 0001 compared to the group of salvinolic acids or the group of Notoginseng root saponins with a value of < 8 0 ..; Compared to the group of salvinolic acids + saponins of notoginseng roots e, Notoginseng m0©...compared to the group of salvinolic acids + saponins of roots. Borneol camphor + Notoginseng

Yves

M. “MCAO Mid-Cerebral Artery Occlusion Table 7 Effects of the pharmaceutical compounds and extracts of the present invention on the area of cerebral involvement in rats (s+x) (MCAO) Groups Dosage 1 qt | Ala 1 (mg/kg of | animal [loa NW} | ligamentum/weight (pend) whole brain (7) | brain damaged part (7) Pharmaceutical composition shown in example 1 (extract Roots Salviae Miltorrhiza + extract of plant roots H+.1+H+? + Camphor, Borneol (The pharmaceutical composition shown in the example ¥ (Extract Salviae sda Miltorrhiza + Root extract | H+.1+M+? V.ouY.

NY | 4 011 ed a+ Notoginseng Nebsat Ye 5577© x » 3457© Astragali + wood oil (Dalbergiae Odoriferae) salvinolic acids + saponins 0+ aE 01 YHYY+1 1 Notoginseng roots + camphor % Eth Borneol Yo acids 07 HT salvinolic elise allll VACHE TERS Notoginseng VTE 41 ATERLYY 1 salvinolic acids ele py om saponins Roots 001 Y.

Notoginseng Nya 07+44 MA 7 Z YYee

m 7.74 114 Ve Y. XUESAITONG ete tL

So]ee [wens > compared to the control group; * M..M “M..1< PEE (00 >P* Note: or the group of root saponins salvinolic acids compared to the group of succinic acids cov) compared to the group of acids ... 1<©** ....# >P * Notoginseng Notoginseng; 8# M<e... Notoginseng Root Saponins + salvinolic acids Notoginseng Root Saponins + salvinolic acids compared to a group of succinic acids © . Bomneol Camphor + Notoginseng The results in Tables 1 and 7 indicate that all the drugs tested have an anti-cerebral ischemia effect. Among all medications; Both the compound of the invention in example 1 (extract of the roots of Salviae Miltorrhiza; the extract of the roots of the plant Notoginseng 0 “the roots of the Astragali plant” and camphor, Borneol) and the compound of the invention in the example ¥ (extract of Salvia miltoriza 1411001128 Salviae ¢ Notoginseng root extract; Astragali root 1 + and Dalbergiae Odoriferae wood oil had remarkable therapeutic effects. Was gl salvinolic acids or Notoginseng root saponins were given A similar effect (sill vo) resulted from giving XUESAITONG (trade name; positive control drug); the therapeutic effects were better when giving the combined compound consisting of salvinolic acids plus Notoginseng root saponins plus Borneol camphor. It died when giving salvinolic acids + notoginseng root saponins or

salvinolic acids alone or Notoginseng root saponins alone or even XUESAITONG (trade name); However, its effects are worse than those resulting from administering the pharmaceutical compound shown in Example 1 and the pharmaceutical compound shown in Example 7.

ge 0 during the use of the myocardial infringement test sample; The present invention can parallel the invented anti-ischemia compositions ai ils of the myocardium; salvinolic acids plus Notoginseng root saponins plus Borneol camphor or Dalbergiae Odoriferae wood oil ¢ salvinolic acids plus Notoginseng root saponins; Salvinolic acids lia asl and

0 Notoginseng root saponins. The results indicate that the current compound has a remarkable effect against ischemia that affects the heart muscle. Where its effects are more effective than the salvinolic acids alone or the notoginseng root saponins and more effective than the salvinolic acids (2) Notoginseng saponins and more effective than the salvinolic acids plus

1 Notoginseng root saponins plus Camphor Borneol or Odoriferae wood oil 156 p:06l02. The results indicate that for the pharmaceutical composition of the present invention - it is better to mix the extract of the roots of the plant Salviae Miltorrhiza plus the extract of the roots of Notoginseng plus the extract of the roots of the Astragali plant and Borneol camphor «or the extract of the roots of the Salviae Miltorrhiza plant plus summary

0 Notoginseng Root plus Astragali Root Extract 1 and Cada Oil Dalbergiae Odoriferae - Remarkable synergistic effect.

Yves

wide -

Experiment 1- Studies on the effects of anti-ischemia compounds of the present invention affecting

Myocardium 1 Collection and administration of the products to be tested: Ve male Wistar rats - weighing approximately 750.8 + YET g -_ are distributed randomly into V drug groups according to their weight: © Physiological saline (control) XUESAITONG ¢ salvinolic acids Notoginseng root saponins Notoginseng ¢ salvinolic acids plus Notoginseng root saponins; Pharmaceutical compounds in example 1, and pharmaceutical compounds in example? All tested drugs are diluted with physiological saline solution to desired concentrations; And the tested drugs are given in the amount of; ml/kg by intravenous injection

caudal yo.

METHOD A. Rat myocardial infringement test model: Rats are anesthetized with pentobarbital sodium (£0 mg/kg) dling through the peritoneum; rats are then fixed in a supine position on the ell and inserted into an endotracheal tube After that, a longitudinal wound ve cm long is incised through the left side of the sternum. After opening the thoracic cavity, the third and fourth ribs are removed, starting from the cartilage of each of them to the sternum.” Breathing is maintained by placing the rat on an artificial respirator (ventilation volume 100 fda) g; 00 times per minute.). The pericardium is removed and the heart is exposed; Then the suture is placed under the left descending coronary artery disease, with the aim of ligation; Then the standard “lead” graphic image is recorded. After stabilization in Ved© minutes;_ the left descending coronary artery is ligated and the thoracic cavity is closed. The material is sucked out

a

—— $ $ —

excreted from the larynx by a syringe; And then sale) rats to self-respiration. 11 minutes later

In coronary artery disease, medications are injected into the gallbladder through a vein.

and after; Hours after coronary artery bypass ligation ‘ the heart is removed from the rat and

Excise the part below the binding thread and cut it into strips, each of which is dipped in nitro tetraxolium blue (NBT) to be stained. The percentage of infringement_area in the myocardium is calculated

In relation to the space of the ventricles and in relation to the heart as a whole; The results are analyzed using the t-statistical method

(test

Based on the isolated perfused heart experiment (Langendorff): Refer to "Experimental Methods in Pharmacology"

Experimental Methodology of Pharmacology” (edited by Shuyun Xu Press).

(YeoF 3rd ed.; People Health Jan. 0 Results 1.”a. Effect on myocardial infringement area in rats; see table

oo — 4 — Table 580 Compounds and extracts of the present invention on rat myocardial infringement zone (MCAO) (find) Groups Dosage | number | infringement in | A a (mg/kg of | animals | myocardium/ cerebral/ heart body weight) whole area (7) ventricle (7) the pharmaceutical composition shown in Example 1 (Salviae root extract: M Nd m na | 0+.+h+? Borneol (Pharmaceutical Composition Shown in Example Y) (Salviae veer root extract | ae 45+17 | No Miltorrhiza + Notoginseng Root Extract + Astragali Root Cag 3+ Dalbergiae plant wood (Odoriferae salvinolic 5 + saponins roots 01 7 + 17 + 7 1 17 + | container 25H x 25H: * Notoginseng + camphor + Bomeol salvinolic acids + Root saponins 7 - 1 + 1 At 1 ¢ ot Y 1 . o At Y 0. o 1 1 0 1 Y . Y . ° sr xx # Notoginseng ELLA 01 Y. salvinolic acids to an extent | VAN £692 * * Saponins Roots 1 0 Y 0 Notoginseng No 9 . ° Y + 0 1 . ¢ Y . A X + Y 1 * * XUESAITONG A 0 above | [es es

Note: >P* 5...; PEE < 1....; compared to the group, Fall all m < ... is # m < 0.01 compared to the group of succinic acids, salvinolic acids, or the group of saponins, roots of gi gill, ginseng, dy Notoginseng, and d MLC<1...; compared to a group of salvinolic acids + Notoginseng root saponins; 8 m<e... Compared to a group of salvinolic acids #Notoginseng root saponins + Camphor Bomeol. B. Effect of a8 on coronary artery disease flow volume and heart rate in an isolated guinea pig heart 01

schedule ; Effect of compounds and extracts of the present invention on coronary artery disease flow volume and heart rate in isolated guinea pig heart (sx) experimental groups | number | Increasing value | The amount (mg/kg_ of | animals | flow volume | decreasing body weight) coming into the artery | Jad mitral pulse (ml/ | heart fn) min) min) The pharmaceutical composition shown in example 1 (Salviae Miltorrhiza root extract + Y+o+ 011 root extract).+o | Notoginseng + Sale Say +*# Astragali Root + Camphor Hl #548 w x vg (Borneol) Pharmaceutical composition shown in Example Y (Extract Salviae Miltorrhiza sia # Root Extract 16441 +3 V+ | Y+o+).+o | Notoginseng * »M8 + Astragali roots + Hrsg aA wood oil |# (Dalbergiae Odoriferae Saponins Roots Notoginseng + Camphor Sug vi Borneol salvinolic acids + root saponins (*q4Y) +4 011 1. ALY 1 and A YYs

M -

Note: >P* 5...; PEF <1.... compared to the control group; 11010056 OR >P * ¢ XUESAITONG H... ¥* cv.

V>P compared to a group of salvinolic acids + saponins of notoginseng roots v.00 >P ey Notoginseng compared to a group of succinic acids Gili lat salvinolic acids notoginseng roots

. Borneol Camphor + Notoginseng. The results in the two tables indicate “? And ; That all the drugs tested have a significant anti-ischemia effect that affects the heart muscle. Among all medications; Show each of the compounds of the invention in ; Salviae Miltorrhiza Root Extract (Salvia Miltorrhiza Root Extract Example 1) Borneol and Camphor ¢ Astragali; miltoriza astragali plant 01 + and sda; Notoginseng root extract of Notoginseng had the best therapeutic effects. It was to give acids (Dalbergiae Odoriferae ada plant) oil Notoginseng or Notoginseng root saponins aa ) salvinolic acids sagein (positive control drug); The effects (XUESAITONG) were similar to the effect resulting from giving therapeutic vo salvinolic acids better when giving the combined compound consisting of succinic acids than when giving Borneol plus camphor Notoginseng saponins Xl or Notoginseng saponins Notoginseng roots + salvinolic acids or saponins of notoginseng roots baal salvinolic acids (trade name) alone, but its effects are worse than XUESAITONG alone or even Notoginseng 0 and Pharmaceutical Compound 1 The effects resulting from the administration of the pharmaceutical compound shown in the example

shown in the example?

Claims (1)

sa — - Claims 1 1 - Pharmaceutical composition comprising: 78.0 to 70056 7 by weight of Y root extract of Salviae Miltorrhiza; Notoginseng wt 85.0 to 0.1 0.1 of Y Astragali to 7 7000 wt Notoginseng Root Extract Toa 0 ? and © Z 15.0 Joey 7 wt. of Borneol or oil from Dalbergiae Odoriferae wherein 1 The root extract of said Salviae Miltorrhiza contains A from 748 to 7970 wt. of salvianolic acid cr salvianolic acids and an amount from 0 to 7 01 by weight of salvianolic acids and from 0 to 0?# by weight of rosmarinic acid 0 e and from 1 to 701 by weight of lithospermic acid and more of 11 7970 by weight of salvianolic acids ¢ 1 and the aforementioned Notoginseng root extract includes an amount of 71 10 of 1/7 by weight of cnotoginsenoside R1 from ZY to 71 7215 to 7460 wt of ginsenoside Rgl 719 to 740 wt 0 of ginsenoside Rbl + 78# to 11 7 wt of ginsenoside Rd and more than 79760 MT of Notoginseng root compounds; And, 11, the product of extracting the roots of the aforementioned Astragali plant includes an amount of 75 to 2059 YA by weight of astragaloside 1 and more than 7970 by weight of root compounds. ,. Astragali Yyeee - 3 ~ 7 15.0 of claim (1); Where it includes an amount ranging from lig? - Composition 1 Salviae Miltorhiza lll ull to ... 7/8 by weight of the root extract of the plant | © Miltorthiza ; .718.0 to 738.0 by weight of ¢ Notoginseng ©¢ – Astragali – .215 to – 0.78 by weight of – 1 – 1 – 1–..77 to 707.001 by weight of Bomeol borneol and oil from Lignium dalpier = Gia .Lignum Dalbergiae Odoriferae | Odorvir 7 30.0 ranges from Jie (comprising oY) formulation pursuant to claim -© 1 to eo by weight of root extract of Will ull Salviae Miltorrhiza | From 77001 to ..758 by weight of Notoginseng ¢ Root Extract © and from 7700.0 to 77000 by weight of Astragali Root Extract; 1 and 74.6 to 70001 by weight From Borneol or oil from Lignium d'Alber - Jia Lignum Dalbergiae Odoriferae (Lignum Dalbergiae Odoriferae A 1 +- formulation (CF) comprising 777 wt. Y. of Salviae Miltorrhiza root extract; ¥ m by weight of Notoginseng root extract; ; 277 by weight of Astragali root extract; and 79 by weight of © Borneol or oil from Lignum Dalbergiae - Gia Odorvera Lignum Dalbergiae Odoriferae 1 Yyee - M1 - 1 #- The composition according to Claim No. (1); where the extract of the roots of the aforementioned Salviae Miltorrhiza plant contains more than 780 by weight of ¥ salvinolic acids; and the extract product includes Hd a Notoginseng plant; - Notoginseng mentioned contains more than 780 by weight of the compounds of the roots of the Notoginseng Notoginseng; and the extract of the roots of the Astragali plant, Astragali > mentioned, contains more than 780 by weight of the saponins of the roots of Astragali, Astragali 1 1 - The composition according to Claim No. (1), where the composition is in the form of a dosage form of an injection 7, or tablets, or sustained-release tablets ~~ ¥ ¢ or drop pills or granules; injection powder ¢ or capsules; or microcapsules .microgranules © 1 7 - Composition pursuant to claim (7); Cun the formulation is a material for injection or (Y) injection powder A) - The use of the formulation according to Claim No. (1) in the manufacture of a drug for the treatment of heart diseases "| Cardiovascular and cerebrovascular .cerebrovascular 1 4- Use of the combination according to Claim No. (Y) in the manufacture of a drug for the treatment of cardiovascular and cerebrovascular diseases. Y — 0 — -01 1 Use of the ly combination of claim No. (7) in the manufacture of a drug for the treatment of cardiovascular and cerebrovascular diseases. 11 1 Use of the composition according to claim No. ) £( in the manufacture of a drug for the treatment of cardiovascular and cerebrovascular diseases (VY). The use of the bs combination of protection element No. (0) in the manufacture of a drug for the treatment of cardiovascular and cerebrovascular diseases .cerebrovascular YY) Use of the combination according to claim No. (7) in the manufacture of a drug for the treatment of cardiovascular diseases 1 Cardiovascular and cerebrovascular 14-1 Use of the composition according to claim No. (7) in Manufacture of a drug for the treatment of heart diseases, cardiovascular and cerebrovascular.